It is known that compounds having a muscarinic receptor antagonist effect induce bronchodilation, gastrointestinal motility inhibition, gastric acid secretion reduction, dry mouth, mydriasis, tachycardia, as well as urinary bladder contraction inhibition.
Between 1983 and 1993, continuous advances were produced in the knowledge of muscarinic receptor pharmacology. During this period, a total of five human genes codifying muscarinic receptor subtypes (m1, m2, m3, m4and m5) were cloned and expressed, which encoded five functional receptors (M1, M2, M3, M4 and M5).
The M1 receptor is a postsynaptic neuronal receptor mainly located in brain and peripheral parasympathetic glands. In smooth cardiac muscle there is a major population of M2 receptors. The M3 receptor is predominantly located in glandular exocrine tissues such as salivary glands. The M4 receptor is mainly present in cerebral cortex, striatum and some peripheral locations in specific species. The M5 receptor has been described in the cerebral vessels. In the smooth muscle of intestinal tract, urinary bladder and bronchus, M2 and M3 receptors coexist. Nevertheless, functional information commonly accepted indicates that the M3 receptor is the responsible for the contractile effect of the endogenous neurotransmitter in the last three tissues.
Few M3 antagonists lacking M2 affinity have been developed. The present invention contributes to fill this need by providing this kind of antagonists.
It seems interesting to obtain M3 receptor selective antagonists to avoid the adverse effects due to blockade of other muscarinic receptors, mainly the cardiac effects due to M2 receptor inhibition. At present, oxybutynin (Alza), trospium (Madaus) and tolterodine (Pharmacia), among others, are commercially available compounds showing reduced selectivity for M2 and M3 receptors. However, darifenacin (Pfizer), and solifenacin (Yamanouchi), both in clinical phase, exhibit M3 antagonist activity with a reduced affinity towards M2 receptor.
In contrast, tiotropium bromide (Böehringer Ingelheim) binds with similar affinity to muscarinic M3 and M2 receptors. However, it dissociates more slowly from M3 than from M2 receptors and subsequently has a long acting effect over M3 receptor. In consequence, it may be considered as a functionally selective M3 antagonist compound.

The following are some patent applications claiming compounds with carbamic structures as selective M3 receptor antagonists: JP 04/95071, WO 9506635, EP 747355, EP 801067 and WO 0200652. All these documents describe carbamates different to those described in the present invention, and the later two describe the structurally nearest to the hereby claimed. In document WO 0104118 some alkylquinuclidinium esters are described as selective antagonist for M3 receptors, but they are also different from the compounds claimed in the present invention.
The compounds claimed in the present invention may be used either alone or in association with other therapeutic agents selected from the group consisting of: calcium channel blockers, α-adrenoceptor antagonists, β2-agonists, dopamine agonists, corticosteroids, phosphodiesterase 4 inhibitors, leukotriene D4 antagonists, endothelin antagonists, substance-P antagonists, antitussives, decongestants, histamine H1 antagonists, 5-lipooxigenase inhibitors, VLA-4 antagonists and theophylline.